The Future of ADCs

Targeted therapeutics, as conceived by Paul Ehrlich at the turn of
the last century, are now a reality with the world’s best-selling drug
(Humira) paving the way for increased development in the biologics
field. The subsequent development of antibody-based therapeutics opened
the floodgates for a variety of targeted drugs (eg, bispecifics,
bi-specific T-cell engagers, designed ankyrin repeat proteins, etc) to
be developed and to expand upon the therapeutic opportunities.
Antibody-drug conjugates (ADCs) now also appear to be capturing the
limelight.

The use of cytotoxic compounds to target cancer cells has been the
mainstay of cancer treatment for over 50 years. Chemotherapy using
cytoxic compounds (both as single compounds and in combination
therapies) have been optimised to maximise patient benefit (1). However,
these agents are limited by systemic toxicity and poor tumour
penetration, resulting in the risk of relapse and the need for further
treatment. The simple concept of monoclonal antibodies targeting
tumour-specific antigens being joined to cytotoxic agents to kill cancer
cells has been muted for many years. Early technology pioneers
developed Mylotarg to treat acute myeloid leukaemia (Pfizer – initially
withdrawn due to toxicity, but recently reintroduced to the market),
Kadcyla® (Genentech) to treat metastatic breast cancer, Adcetris® to treat Hodgkin’s Lymphoma (Seattle Genetics), and, more recently, Besponsa® (Pfizer), but these are widely considered to have drawbacks (2-3). One
challenge for ADCs has been obtaining a reasonable therapeutic window
where the toxicity conveyed by factors such as instability or off-site
binding outweighs the clinical benefit. To overcome such challenges, new
technologies are emerging that address the three fundamental components
of these molecules: the antibody, the cytotoxic payload, and the linker
that joins all the components together (see Figure 1). With each
technology iteration associated with these three components improving
efficacy and safety, the prospect for this class of therapies is bright.
This article will discuss the new technologies emerging that may
address the shortfalls in early ADC development and thereby increase the
numbers gaining approval.

Selection of Antibodies

The selection of an appropriate antibody is still a vague science
associated with development of a suitable ADC. Antibody specificity to
minimise off-site binding and to generate as large a therapeutic index
as possible is of critical importance. Further to this, internalisation
of the antibody is also vital to ensure the toxic payload is delivered
to the appropriate location. The required affinity of the base antibody
has been reported to be of lesser importance, with high affinity
antibodies sticking to the surface of tumour cells resulting in limited
tumour penetration, whereas lower affinity antibodies have been shown to
reflect better tumour penetration (4-5). To date, most ADCs have
affinities in the range of 0.1-1nM, but the uncertainty surrounding the
best antibody selection suggests the testing of large panels of
antibodies with diverse affinities may be the most rational strategy
during early development. As ADCs evolve, other contributing features to
enhance function are also being considered. For example, the use of an
IgG1 isotype may encourage antibody-dependent cell-mediated cytotoxicity
(ADCC) and/or complementdependent cytotoxicty (CDC) activity and
additional cell lysis. Such activity may subsequently lead to cytotoxic
metabolites or released cytotoxic payload diffusing into surrounding
cells and assisting cell killing in the tumour environment − the
so-called ‘bystander effect’ (9).

Dr Neil Butt has over 20 years’ experience in the biotechnology industry, covering both research and business development. His industrial experience started in R&D before joining PA Consulting where he focused on business development and operational roles in the biotech sector. Neil then joined the executive management team of Antitope as Head of Business Development. During his tenure, he was key to the company’s growth and helped steer them through the acquisition by Polytherics. Neil was then appointed Head of Business development and was part of the executive management team that oversaw the rebranding as Abzena. He joined IONTAS in 2016 as Chief Business Officer.

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Key to Outsourcing Method Development and Validation: A Pragmatic Approach

RSSL

In an industry that is seeing an increasing level of work being outsourced, the Contract Research Organisation (CRO) of choice needs to have proven experience in both the pragmatism and flexibility of the method developer’s mind set and a regulatory background in validation.
As companies are focussing on achieving ever shorter times of drug to market, it is vital that a tailored, pragmatic approach is adopted when engaging in both method development and validation activities for an Active Pharmaceutical Ingredient (API) or drug product (DP).
Although methods still require a high degree of robustness, the overall strategy should encompass a full evaluation of the regulatory requirements applicable to the particular phase of the drug life-cycle; this is pivotal in Key to Outsourcing Method Development and Validation A Pragmatic Approach order to ensure a successful regulatory submission, where the applicant must demonstrate suitable validation of all methods used to support the filing.
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